人口药物动力学和对实体肿瘤患者cobimetinib剂量的影响。

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汉K金司法院玛珊德M,普尔酒馆年代,忠N,黑客SP, Tikoo N,布鲁诺R,梳妆台,Musib L, Budha NR

人口药物动力学和对实体肿瘤患者cobimetinib剂量的影响。

癌症Chemother杂志。2015年11月,76 (5):917 - 24。doi: 10.1007 / s00280 - 015 - 2862 - 0。Epub 2015年9月13日。

PubMed ID

26365290 (在PubMed

]

文摘

目的:描述cobimetinib药物动力学和评估临床相关的协变量对cobimetinib药动学的影响。方法:血浆样本(N = 4886)收集从487年各种实体肿瘤患者(主要是黑色素瘤)在三个临床研究(MEK4592g, NO25395 GO28141)。Cobimetinib口服药物,每天一次在21-day-on / 7-day-off, 14-day-on / 14-day-off或28-day-on安排在28天给药周期单剂或结合vemurafenib。Cobimetinib剂量范围从2.1到125毫克。NONMEM用于药代动力学分析。结果:与一阶线性两舱制模型吸收,消除滞后时间和一阶描述cobimetinib药物动力学。明显的典型估计(inter-individual可变性)间隙(CL / F),中央的体积分布(V2 / F)和终端的半衰期是322天信用证(58%),分别为511 L(49%)和2.2天。Inter-occasion变化相对生物利用度约为46%。CL / F随年龄下降。V2 / F与体重增加(BWT)。 However, the impact of age and BWT on cobimetinib steady-state exposure (peak and trough concentrations and AUC following the recommended daily dose of 60 mg 21-day-on/7-day-off) was limited (<25 % changes across the distribution of age and BWT). No significant difference in cobimetinib pharmacokinetics or steady-state exposure was observed between patient subgroups based on sex, renal function, ECOG score, hepatic function tests, race, region, cancer type, and co-administration of moderate and weak CYP3A inducers or inhibitors and vemurafenib. CONCLUSION: A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.

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药物

Cobimetinib